Gene Therapy for Rare Disorders

Christina Lingham:
Hi everyone. I'm Christina Lingham of Cambridge Healthtech Institute. I'm really pleased to have the opportunity to speak with Peter Marks, Director of the Center for Biologics Evaluation and Research at the FDA, to talk with us about his featured presentation on facilitating the use of gene therapy for rare disorders. He'll be giving a keynote on the Renaissance of Gene Therapy and Gene Editing track this March 2nd through 4th in San Francisco, California.

Peter, thank you for joining us. Can you please introduce yourself to our audience? Your work and what you do?

Peter Marks:
So I'm Peter Marks, Director of the Center for Biologics Evaluation and Research at the US Food and Drug Administration. And we regulate a variety of complex biologic products, including blood products, vaccines, and cell and gene therapies. And we're involved in both the regulatory policy making, the execution of the regulations, the review and approval of products, as well as on doing applied scientific research on the products that we regulate.

Christina Lingham:
Your talk is about facilitating the use of gene therapy for rare disorders. Can you briefly describe the scope of your work?

Peter Marks:
So one of the key areas that we're very interested in today are helping to move ahead the production and the availability of gene therapies for rare disorders that are treating very small populations. To date, gene therapies have been used for small populations, traditionally considered orphan diseases, less than 200,000 in the US. But there are some very, very small populations, populations of perhaps less than 100 individuals per year, that might use gene therapies. And we're very interested in helping to have people gain access to those. In part because right now, those are not really commercially viable. So those are not things that people are going to develop in the absence of some incentive to do so.

Christina Lingham:
Can you outline what are some of the greatest obstacles to developing gene therapies, and specifically for rare disorders?

Peter Marks:
Well, obviously there are various places that there can be obstacles when you're developing a product. Traditionally, we've always thought of clinical development as one of the larger areas that can be an obstacle to product development. But for gene therapies, particularly when they're targeted to a single gene disorder, the clinical development is often not as complicated. It's a matter of getting safety information on the product and then having enough people treated to know that you're having a reproducible treatment effect.

The larger problem right now as the issue is really the fact that it's challenging to manufacture gene therapies, and that's because the gene therapy vectors are not made efficiently in cell lines currently. Purifying the gene therapy products is a relatively complex process and it's not yet fully standardized. And so that is one of the largest obstacle, that is actually getting the product made so that they actually can be tested in humans, and then obviously made available over the longer term. The capacity of the system right now, at least in the United States, to make gene therapies for these small batches is not sufficiently great. In other words, there's pent up demand for making them.

Christina Lingham:
What do you consider some of the most exciting emerging developments in the field?

Peter Marks:
With genome editing, one is able to make changes in the cells that potentially allows one to have allogeneic cells. That is essentially product that could be off the shelf, and that's because once you make the multiple changes that's necessary in order to have such a product, and potentially have it be effective, genome editing may also open up the realm of kinematic antigen receptor T-cells for the treatment of regular standard oncology diseases as opposed to just hematologic diseases that is solid tumors as opposed to just...

Christina Lingham:
What message do you want to convey to the gene therapy CRISPR CAS nine and gene editing audience.

Peter Marks:
I think the important message here is it's a tremendously exciting time. I think the FDA is very interested in facilitating the efficient development of these products. We're going to do so and make sure that the products that get out there are both safe and effective. That may mean that it may go slower than some wants because we will have to make sure that we can walk before we can run in terms of the safety of these products. Because genome editing does have the potential for off target effects and until we really have a good handle on those, we'll probably be a little cautious as we move forward. Nonetheless, I wouldn't want anyone to think that we're not very excited about moving forward in this area.

Christina Lingham:
What are some of the novel approaches you are excited about in manufacturing or preclinical and clinical development?

Peter Marks:
So let me give you an example in each of these. I think in manufacturing, I think that there may be improvements in both the cell lines and the cell culture technology to help increase the yield of these products. I also think that we may see better purification processes developed that will allow for a purer product that will be more reproducibly efficacious. So I think there's plenty of room for improvements in manufacturing and I think those technologies are there. It's a matter of putting it all together and doing some additional work on the cell lines.

I think in the preclinical area, I think we see horizon now the potential use of human organoids, which may allow the testing for off target effects in a way that one simply can't do in animal models. If you're doing CRISPR CAS nine is genome editing, you'd like to use a human genome and not a mouse or a baboon or some other genome if that's what you're really interested in. By using these organoids when they get a better idea of what's going on then using a live animal model. And then falling on the clinical end, we're really excited about people starting to apply novel clinical trial design, including starting to use a complex innovative trial designs that might involve Bayesians statistics so that one can try to come to a decision about whether a product is going to be effective or not in the smallest number of people enrolled in the trial.

Christina Lingham:
Aside from profit and manufacturer costs and major contributor to therapeutic pricing costs is the running of clinical trials. Now that we are equipped with programmable and thus personalizable editing enzymes that are being enthusiastically evaluated for the general safety properties. How do you imagine the regulatory landscape around therapeutics that are truly personalized? For example, how will trials be conducted when tailored for patient's unique mutation?

Peter Marks:
Yeah, so these therapies, I like to describe them more as individualized and personalized, personalized medicine. We think of medicines on the shelf that one takes off and then applies to people. Here we're actually making medicines for the individual. Nonetheless, it's a great question because one is going to potentially have the same disease entity, which is caused by multiple different mutations that one might address with different CRISPR CAS nine constructs. They all may be related and so it will be the CRISPR CAS nine guide that will be different in some vector that will be the same. And figuring out a regulatory path forward for this is one of the important things that we're working on now. Ideally, one would like to be able to do is take one product and bring it through with a robust clinical development package and then have a way that the rest of the changes might be put through potentially even without clinical data.

If one could make a compelling case that they produce the same effect. One might get the clinical data on the back end after they were in use, so we still don't have anything firmed up, but we're trying to think about novel approaches where we could facilitate this. Obviously making sure that safety was maintained but also trying to make sure that we weren't making it very difficult to deal with the fact that there could be very slight changes, one per two base pairs necessary in different constructs to address different mutations and this is something that we would be willing to try to consider kind of through these novel pathways. Probably with the most important information coming regarding whether there were new off target effects introduced by changing the guys.

Christina Lingham:
Well this sort of medicine forever exist in investigational territory, or might it warrant a new regulatory track where preclinical testing is done in patient derived cells in the lab to get a sense of the genomic impact before administration?

Peter Marks:
That's a great question. Our goal is to help at least get as many of these out of the investigational attract and then into an approved track by facilitating the regulatory framework to allow the products to get approved by understanding that they're both safe and effective. Now there may be some products destined to treat very, very, very small populations that will perpetually be an investigational domain. We have those now. There are products like anti-venoms that are perpetually under investigation and drug application. That being said, ideally in this area, we'd like to see the products developed to a point that we can see both a lead product and then perhaps the variety of different gene targeting constructs that might be, Oh, a class of 20 or 30 or even 40 different products that are all related, be able to be on the market and be commercially viable.

Obviously that's going to take some work in our regulatory framework, but I think because we have a headstart on this, as the products are starting to be conceived of now, we should be in a reasonably good place. I think one of the lucky things we've been able to do is get a head start here on thinking about the regulatory frameworks that will be necessary to accommodate this type of commercial products where you're going to have really classes of products that are very closely related, treating one disease.

Christina Lingham:
On the topic of pricing, how can we justify and sustain the absorbent and price tax, one to $2 million on some new therapies like Zolgensma.

Peter Marks:
So FDA doesn't traditionally directly address pricing issues. We approved products irrespective of their price, but we're very much aware of them, the price. And our goal is to hopefully see the prices of these products coming down by seeing their production more efficient. All that said, these price tags of one to $2 million. On the one hand one can say, wow, that's an incredible cost. On the other hand when you realize that Zolgensma, which is how a product, that type of spinal muscular atrophy that normally killed children by the time they're two or three years old. And when you see the clinical results that is you can see now three or four year old children who were treated with it when they were infants who are for all you can tell normal, very hard to put a price tag on that for the parents particularly but also for medicine in general.

So I think what we're going to have to see is us becoming better at making these more efficiently. I think in some ways this is going to be something that society will have to grapple with, but we're very happy right now to try to keep these products coming towards market with the hope that the more a product on the market, the more efficiently they're produced, the lower the prices of the more reasonable these prices will come.

Christina Lingham:
Lastly, can you talk about the scope of the FDA's dominion in the case of heritable genetic modifications. For instance, we are confronted with the new reality of designer babies and edited babies.

Peter Marks:
So this is a tremendously controversial area. In United States, currently the introduction of heritable genetic modifications is not allowed and that's by appropriations writer, which prohibits FDA from accepting applications that try to do heritable genetic modifications. Now obviously globally, this was tried in China and there were some repercussions for it. There's also a National Academy of Sciences and WH Show engagement currently trying to address this issue because it's obviously quite concerning to many that although one might say, well it would be wonderful to correct some of the heritable diseases that cause a tremendous amount of suffering. There's also the issue that then you could have designer babies and so trying to understand whether it's ever going to be reasonable to go down that path is something that emphasis politicians and others are currently debating. From our perspective right now, we simply are the ones that are obeying and carrying out what is the policy in the United States, which is that there is no heritable genetic modifications allowed in humans at this time.

Christina Lingham:
Peter, thank you for your time and insights today. That was Peter Marks of the FDA. He'll be the featured speaker in the Renaissance of gene therapy and gene editing track this March. If you'd like to hear him in person, go to tryconference.com for registration information and enter the key code podcast. Thanks for listening.


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